Modern lifestyle, often characterized by over-nutrition and lack of exercise, causes prolonged activation of mTOR complex 1 (mTORC1)/S6K and chronic suppression of mTORC2/AKT, which together promote age-related muscle pathologies including insulin resistance, fat accumulation, mitochondrial dysfunction and functional decline. Using Drosophila as a model organism, we recently found that Sestrin acts as an important regulator of both mTOR complexes, and that the absence of Sestrin brings about several age-associated pathologies including mitochondrial dysfunction and skeletal/cardiac muscle degeneration. Sestrin dependent regulation of mTOR complexes is important for maintaining muscle health throughout life. We hypothesize that Sestrin can be a novel molecular target in the mTOR signaling network that can limit chronic mTORC1 activation and preserve mTORC2 activity in muscle, thereby promoting life- and healthspan. Transgenic induction of Sestrin in skeletal and cardiac muscle can prevent age-dependent loss of endurance and mobility, while increasing speed, endurance and cardiac performance. Importantly, endurance exercise induces Sestrin expression, while Sestrin deficiency nullifies the effects of long-term exercise in improving mobility and metabolism. These data suggest that Sestrins may mediate the beneficial effects of exercise in preserving muscle health, making the Sestrin protein family a potential therapeutic target for preserving mobility and improving quality of life in later ages.